The objective of this research is to study the metabolism of carcinoembryonic antigen (CEA) and improve the clinical usefulness of CEA in the early detection and management of cancer. CEA metabolism is a unique complex multistage process. Initial clearance from the circulation is by the Kupffer cell followed by transfer to the hepatocyte where degradation in the lysosomes occurs. We have identified a binding protein on the Kupffer cell specific for CEA and the related glycoprotein NCA. The part of the CEA molecule responsible for binding to the Kupffer cell has not been identified. This will be studied by producing glycopeptides from CEA both chemically and enzymatically and investigating their binding properties to the cell. Similarly it is not known how the Kupffer cell modifies the CEA before exocytosis and uptake by the hepatocyte. This will be investigated by analyzing CEA following exposure to Kupffer cells in vitro and by studying the binding of this modified CEA to hepatocytes. CEA binding to other macrophages will be studied including studies of human alveolar macrophages. The observation that some cancer patients produce a slower clearing CEA and the relationship between their structure, metabolism and the ability to bind to Kupffer cells and hepatocytes will be studied. These studies may result in ways to inhibit CEA clearance reversibly thereby raising plasma levels and allowing earlier detection and monitoring of CEA producing cancers. (1)